Spontaneous preterm birth (sPTB) affects 10-15% of pregnancies and causes the majority (~80%) of neonatal mortality and morbidity. A logical therapeutic strategy to prevent sPTB is to block preterm labor. We propose that this may be achieved by exploiting the pro-gestational actions of the steroid hormone progesterone (P4). Clinical studies showing that prophylactic P4 therapy decreases the incidence of preterm birth, demonstrate the therapeutic potential of targeting P4 to prevent preterm birth. Current therapies, however, are effective in only a small subset of pregnancies. Our goal is to improve prophylactic P4 therapy so that it prevents preterm birth in all pregnancies. To do this the proposed research builds on 4 data-driven concepts: 1) that labor is secondary to tissue-level inflammation within the myometrium; 2) that P4 promotes myometrial quiescence by repressing myometrial inflammation via anti-inflammatory effects in myometrial cells; 3) labor is triggered by functional P4 withdrawal whereby myometrial cells become refractory to P4 anti-inflammatory activity, and 4) functional P4 withdrawal is induced by phosphorylation of the type-A P4 receptor (PR) isoform, PR-A, at serine-344 and -345 (pSer344/345-PRA). In this context, our core hypothesis is that selective progesterone receptor (PR) modulators (SPRMs) that enhance the anti-inflammatory (and therefore pro-gestational) actions of PR and simultaneously inhibit the generation of pSer344/345-PRA (and therefore functional P4/PR withdrawal) will prevent sPTB. Our objective is to identify SPRM compounds with these properties. This will be achieved by addressing 2 Specific Aims: 1) use known SPRM structures to develop compounds that exert PR-mediated anti-inflammatory activity and inhibit pSer344/345-PRA generation in myometrial cells; and 2) identify SPRM compounds (from Aim 1) that inhibit inflammation-induced parturition in the mouse. Our preliminary data support the core tenets of our central hypothesis and we have identified 8 SPRM compounds that exert PR- mediated anti-inflammatory activity in myometrial cells and one compound that decreases the incidence of inflammation-induced parturition in the mouse. Our analysis plan focuses on translational potential of SPRMs for the prevention of sPTB using a stringent SPRM screening regimen involving human myometrial cells and a mouse model for inflammation-induced parturition. Our goal is to develop 10-15 lead compounds. The project has significant translational potential because it is the foundational study for the development of safe, inexpensive SPRM-based prophylactic therapies to reduce the incidence of sPTB in all women.